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PMID: 19956697 Published · epublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S.

HIV- 1 protease inhibits Cap- and poly(A)-dependent translation upon eIF4GI and PABP cleavage.

PloS one ·Vol. 4 ·No. 11 ·2009-11-24 ·Pages e7997

Castelló A, Franco D, Moral-López P, Berlanga JJ, Alvarez E, Wimmer E, Carrasco L

Abstract

A number of viral proteases are able to cleave translation initiation factors leading to the inhibition of cellular translation. This is the case of human immunodeficiency virus type 1 protease (HIV-1 PR), which hydrolyzes eIF4GI and poly(A)-binding protein (PABP). Here, the effect of HIV-1 PR on cellular and viral protein synthesis has been examined using cell-free systems. HIV-1 PR strongly hampers translation of pre-existing capped luc mRNAs, particularly when these mRNAs contain a poly(A) tail. In fact, HIV-1 PR efficiently blocks cap- and poly(A)-dependent translation initiation in HeLa extracts. Addition of exogenous PABP to HIV-1 PR treated extracts partially restores the translation of polyadenylated luc mRNAs, suggesting that PABP cleavage is directly involved in the inhibition of poly(A)-dependent translation. In contrast to these data, PABP cleavage induced by HIV-1 PR has little impact on the translation of polyadenylated encephalomyocarditis virus internal ribosome entry site (IRES)-containing mRNAs. In this case, the loss of poly(A)-dependent translation is compensated by the IRES transactivation provided by eIF4G cleavage. Finally, translation of capped and polyadenylated HIV-1 genomic mRNA takes place in HeLa extracts when eIF4GI and PABP have been cleaved by HIV-1 PR. Together these results suggest that proteolytic cleavage of eIF4GI and PABP by HIV-1 PR blocks cap- and poly(A)-dependent initiation of translation, leading to the inhibition of cellular protein synthesis. However, HIV-1 genomic mRNA can be translated under these conditions, giving rise to the production of Gag polyprotein.

MeSH Terms
Encephalomyocarditis virus/genetics Eukaryotic Initiation Factor-4G/metabolism Gene Products, gag/chemistry HIV Protease/metabolism HeLa Cells Humans Hydrolysis Luciferases/metabolism Plasmids/metabolism Poly A/metabolism Poly(A)-Binding Proteins/metabolism Protein Biosynthesis RNA, Messenger/metabolism Recombinant Proteins/metabolism Reverse Transcriptase Polymerase Chain Reaction
Chemicals
EIF4G1 protein, human Eukaryotic Initiation Factor-4G Gene Products, gag Poly(A)-Binding Proteins RNA, Messenger Recombinant Proteins Poly A Luciferases HIV Protease p16 protease, Human immunodeficiency virus 1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Castelló Alfredo
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, Spain.
Franco David
Moral-López Pablo
Berlanga Juan J
Alvarez Enrique
Wimmer Eckard
Carrasco Luis
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0007997
Published
2009-11-24
Epub
2009-00-24
Pages
e7997
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2776998
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0007997 PMC Full Text View journal details
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